tbuckley/cabot-search huggingface dataset:
Abstract P3026: The Effects Of Diet Modification On The Progression Of Heart Failure With Preserved Ejection Fraction
Authors: Jae Hyung Cho, Isabelle Pellot, Myung Yoon Kim, Asma Nawaz, Eduardo Marbán, Eugenio Cingolani
Journal: Circulation Research (2022)

Introduction: Hypertension is a major risk factor for the development of heart failure with preserved ejection fraction (HFpEF). A high-salt diet has shown to induce hypertension and HFpEF in Dahl salt-sensitive rats; however, once developed, it is unclear if HFpEF resolves after a return to low-salt diet. Hypothesis: Dietary modification to reduce salt content will decrease blood pressure and lead to resolution of HFpEF in Dahl salt-sensitive rats. Methods: Dahl salt-sensitive rats (n=12) were fed a high-salt (HS) diet (8% NaCl) from 7 weeks of age to induce HFpEF. Rats fed a normal-salt (NS) diet (0.3% NaCl; n=6) served as controls. The development of HFpEF was verified with an echocardiogram at 14 weeks of age in HS-fed rats. HS diet was then switched to NS diet in a subset of the HFpEF rats (HFpEF s/p NS, n=6) at 16 weeks of age, while the rest of the HFpEF rats continued to consume HS diet (HFpEF s/p HS, n=6). Blood pressure was measured non-invasively using a tail artery cuff. Echocardiography was performed to measure systolic and diastolic function. Programmed electrical stimulation was performed to induce ventricular arrhythmias. Results: In rats with HFpEF, a switch to NS diet improved diastolic function (E/E’ ratio 14.9±3.0 in HFpEF s/p NS vs. 25.3±8.2 in HFpEF s/p HS, p=0.045). However, the diet switch did not reduce systolic blood pressure (204±15 mmHg in HFpEF s/p HS vs. 194±21 mmHg in HFpEF s/p NS, p=0.44). Lung congestion was also significantly reduced after NS diet in rats with HFpEF (lung/body weight 0.39±0.03% in HFpEF s/p NS vs. 0.50±0.06% in HFpEF s/p HS, p=0.0040). Ventricular arrhythmia inducibility did not change after diet switch (100% in both HFpEF s/p HS and HFpEF s/p NS rats), nor did the duration of induced ventricular arrhythmias (75±3 beats in HFpEF s/p HS vs. 67±8 beats in HFpEF s/p NS, p=0.0749). QTc intervals did not decrease after diet changes in rats with HFpEF (226±29 ms in HFpEF s/p HS vs. 225±4 ms in HFpEF s/p NS, p=0.095). Conclusions: Diet modification improves diastolic function and reduces pulmonary congestion in Dahl salt-sensitive rats with HFpEF, but it did not reduce blood pressure or inducibility of ventricular arrhythmias. Further mechanistic study is warranted to further investigate the effects of diet on HFpEF progression.
Abstract P3067: Sleep Deprivation In Obesogenic Setting Alters Lipidome And Microbiome Toward Suboptimal Inflammation In Acute Heart Failure
Authors: Ganesh V Halade, Yusuf Mat, Siddabasave Gowda B Gowda, Shalini Jain, Shu-Ping Hui, Hariom Yadav, Vasundhara Kain
Journal: Circulation Research (2022)

Introduction: Sleep is fundamental medicine for cardiac homeostasis and the immune fitness of human health. Sleep-deprived individuals are prone to higher incidences of a heart attack. The lipid-dense diet (obesogenic diet-OBD) is a cumulative risk factor for chronic inflammation in cardiovascular disease, thus understanding how sleep fragmentation (SF) in obesity setting impacts immune and cardiac health is an unmet medical need to develop novel therapeutics. Hypothesis: We hypothesized whether the co-existence of SF with OBD dysregulates gut homeostasis and leukocyte-derived reparative mediators thereby impairing cardiac repair. Methods: Two months old male C57BL/6J mice were randomized into two main groups; control (fed standard lab chow) and OBD (fed 10% w/w safflower oil-enriched diet) for 2 months. For SF, mice were subjected to SF chamber (2-minute interval bar sweep in light period (0700–1900 h) for 3 days. Mice of control, control+SF, OBD control, OBD+SF groups were further subjected to permanent coronary artery ligation to induce acute heart failure. Results: OBD fed mice had higher levels of plasma linolenic acid with a decrease in eicosapentaenoic acid and docosahexaenoic acid. The OBD mice had lower levels of Lactobacillus johnsonii indicating loss of probiotic microbiota. SF in OBD mice increased Firmicutes/Bacteroidetes (F/B) ratio indicative of a detrimental change in SF-directed microbiome signatures. OBD+SF group increased in the neutrophil: lymphocyte ratio suggestive of suboptimal inflammation. As a result of SF, resolution mediators (RvD2, RvD3, RvD5, LXA 4 , PD1, and MaR1) decreased and inflammatory mediators (PGD 2 , PGE 2 , PGF 2a , 6k-PGF 1a ) were increased post- MI in OBD fed mice. At the site of infarction, the proinflammatory cytokines; Ccl2, IL1β , and IL-6 were amplified in OBD+SF indicating a robust proinflammatory milieu. OBD+SF group showed signs of neutropenia in the spleen with pre-activation of CD169 macrophages. Also, brain circadian genes ( Bmal1, Clock) were downregulated in SF subjected control mice but remained elevated in OBD mice post-MI. Conclusion: SF superimposed on obesity dysregulated physiological inflammation and disrupted resolving response thereby impaired cardiac repair and signs of pathological inflammation.
Abstract GS102: Injection Of Human IPSC-derived Cardiac Cells Promote Cardiac Repair After Infarction In Nonhuman Primates
Authors: Yu-Che Cheng, Marvin Hsieh, Chen-Ju Lin, Cindy M Chang, Ching-Ying Huang, Riley Puntney, Amy Moy, Ting Chien-Yu, Darien Chan, Martin Nicholson, Jen-Hao Lin, Po-Ju Lin, Hung-Chih Chen, Gina Kim, Jennifer Coonen, Yen-Wen Liu, Timothy A Hacker, Timothy Kamp, Patrick C Hsieh
Journal: Circulation Research (2022)

Introduction: Injection of induced pluripotent stem cell-derived cardiomyocytes has been reported as a promising approach to regenerate loss myocardium and restore heart function after ischemic injury. However, immaturity of the transplanted cardiomyocytes and their poor survival rates caused by limited blood supply remain as major hurdles for clinical translation. Hypothesis: We tested the hypothesis that co-culture of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) with hiPSC-derived endothelial cells (ECs) promotes CM maturation in vitro, and that co-transplantation of both hiPSC-CMs and hiPSC-ECs facilitates hiPSC-CM muscularization in myocardial ischemic injured mice and non-human primates. Methods and Results: We examined the therapeutic effect of co-transplantation of hiPSC-CMs and hiPSC-ECs in NOD-SCID mice undergoing myocardial infarction (N = 14 / group). Mice receiving co-transplantation had an improvement in ejection fraction compared to control (4.2 ± 1.2 % vs -8.4 ± 0.9 %, P &lt; 0.0001), and even those receiving high-dose (-0.3 ± 0.9 %, P = 0.052) and low-dose (-2.4 ± 1.1 %, P = 0.001) hiPSC-CMs alone treatment. Moreover, less arrhythmic events were observed in co-transplantation using three-lead electrogram. To be more clinically relevant, we first showed in healthy non-human primates (N = 4) that hiPSC-CM engraftment, maturation, and integration was achieved when co-transplanted with hiPSC-ECs. Furthermore, we then examined the therapeutic effect of co-transplantation of hiPSC-CMs and hiPSC-ECs in rhesus macaques undergoing ischemia-reperfusion surgery (N = 3 / group). Consistent with the mouse model, co-transplantation in rhesus macaques significantly improved the ejection fraction (10 ± 1.3 % vs -1.8 ± 2.2 %, P = 0.010), accompanied by a reduced infarct size compared to control (16 ± 1.1 % vs 23 ± 3.3 %, P = 0.091). Conclusions: This study demonstrates the beneficial effects of co-transplantation of hiPSC-CMs with hiPSC-ECs, promoting hiPSC-CM maturation, enhancing neovascularization, and improving cardiac function in both mouse and non-human primate hearts. Delivery of this combined cell therapy holds promise for future clinical translation.
Abstract P1019: <i>CycleTrack</i> , A Genetic Method To Trace Cardiomyocyte Renewal In Small And Large Animal Models
Authors: Ilaria Secco, Ana Backovic, Simone Vodret, Matteo Dal Ferro, Mateusz Tomczyk, Khatia Gabisonia, Lucia Carlucci, Lorena Zentilin, Serena Zacchigna, Fabio A Recchia, Mauro Giacca
Journal: Circulation Research (2022)

To what extent cardiac renewal occurs in adulthood and can be stimulated by therapeutic interventions is still a matter of investigation. In particular, over the last few years, significant effort has been made into awakening the endogenous regenerative potential of the adult mammalian heart after injury using different strategies. However, these studies are significantly hindered by the lack of tools to properly assess cardiomyocyte renewal over time. We have developed a genetic strategy, which we named CycleTrack, allowing a cumulative and accurate estimate of cardiomyocyte divisions in vivo. This method is based on the expression, in cardiomyocytes, of the Cre recombinase under the control of a 312-bp fragment of the Cyclin B2 promoter, which is specifically sensitive to cell proliferation. Replication-activated Cre acts on floxed GFP that is either present in the genome of transgenic mice or is exogenously delivered using Adeno-Associated Viral (AAV) vectors. As a result, cardiomyocytes traversing G2/M become irreversibly labeled. Using CycleTrack, we could monitor cardiomyocyte turnover in several physiological and pathological conditions. These included the measurement of the rate of proliferation of cardiomyocytes after apical resection in neonatal mice, the pro-regenerative effect of AAV9-mediated delivery of miRNA-199a and miRNA-590 after myocardial infarction in adult mice and the effect of pregnancy on myocardial hyperplasia. We also delivered the CycleTrack vectors into pig hearts to visualize cardiomyocyte turnover after myocardial infarction. Considering the large availability of Cre reporter mouse lines and the efficacy of AAVs to transfer genes into cardiomyocytes, we propose CycleTrack as a robust and straightforward tool to trace mitotic events for cardiac regeneration studies in small and large animal models.
Abstract P3127: Wnt1-inducible Signalling Pathway Protein 1 Contributes To Vascular Fibrosis By Promoting Fibroblasts Phenotypic Switch And Extracellular Matrix Deposition
Authors: Ze Li, Helen Williams, Jason Johnson, Sarah George
Journal: Circulation Research (2022)

Background: Vascular fibrosis is linked with many diseases, including hypertension. Upon pathophysiological stimulation, fibroblasts undergo phenotypic switch and increase extracellular matrix (ECM) synthesis and deposition. Wnt1-inducible signalling pathway protein 1 (WISP-1) is a growth factor implicated in fibrotic remodelling. We tested the hypothesis that WISP-1 induces cardiac fibroblast activation and increases ECM deposition, thereby contributing to vascular fibrosis in hypertension. Methods and Results: Primary human cardiac fibroblasts (HCFs) were treated with recombinant WISP-1. Western blotting analysis showed that WISP-1 treatment for 30 minutes activated Akt pathway (phospho-Akt:total-Akt, fold change: 1.33±0.14 vs. 1.00±0, n=9, P &lt;0.05). WISP-1 induced Akt phosphorylation was inhibited by an integrin β1 blocking antibody (phospho-Akt:total-Akt, fold change, 0.52±0.12 vs. 1.00±0, n=5, P &lt;0.05). WISP-1 treatment for 24 hours induced collagen 1 maturation in conditioned media and coincided with decreased meprin α metalloproteinase protein levels (fold change: 0.44±0.14 vs. 1.00±0, n=5, P &lt;0.05). The collagen maturation was inhibited by a zinc-mediated proteinase inhibitor (GM6001) or an Akt inhibitor. Additionally, immunocytochemistry analysis illustrated that 24-hour WISP-1 treatment increased the percentage of α-smooth muscle actin-positive HCFs compared to the control (1.89±0.37 vs. 1.00±0, n=8, P &lt;0.05). In vivo , WISP-1 knockout mice exhibited reduced collagen 1 content (0.39±0.09 vs. 1.19±0.25, n=5-7, P &lt;0.05) and proteoglycan content (2.20±0.37 vs. 6.22±1.10, n=5-7, P &lt;0.05,) in the perivascular area compared to their wild-type control after 28 days angiotensin II (1000ng/kg/min) infusion. Conclusions: WISP-1 activates cardiac fibroblasts via integrin β1-Akt pathway and meprin α metalloproteinase, thereby inducing fibroblast phenotypic switch and promoting collagen deposition. Deletion of WISP-1 alleviated hypertension induced vascular fibrosis in vivo . Modulation of WISP-1 levels may be beneficial for attenuating the effects of hypertension on vascular fibrosis, and could provide potential therapeutic targets in clinical treatment.
Markov blankets as boundary conditions: Sweeping dirt under the rug still cleans the house
Authors: Javier Sánchez-Cañizares
Journal: Behavioral and Brain Sciences (2022)

Abstract Bruineberg et al. underestimate the ontological weight of Markov blankets as actual boundaries of systems and lean toward an instrumentalist understanding thereof. Yet Markov blankets need not be deemed mere tools. Determining their reality depends on the fundamental problem of distinguishing between system and environment in physics, which, in turn, demands a metaphysical bedrock backed by a realist stance on science.
Relationship of the type of tobacco and inhalation pattern to pulmonary and total mortality
Authors: P Lange, J Nyboe, M Appleyard, G Jensen, P Schnohr
Journal: European Respiratory Journal (1992)

Data from The Copenhagen City Heart Study, a prospective population study, were analysed to investigate the influence of the type of tobacco and inhalation on pulmonary and total mortality. The study sample comprised 6,511 men and 7,703 women, selected randomly after age-stratification from the general population. There were 2,986 plain cigarette smokers, 3,222 filter cigarette smokers, 1,578 smokers of cheroots/cigars, 433 male pipe smokers and 773 subjects smoking more than one type of tobacco. From 1976 until the end of 1989, 2,765 subjects died. Lung cancer was considered as main death cause in 268. Chronic obstructive pulmonary disease (COPD) was considered as the main cause in 94 cases and main or contributory cause of death in 195 cases (COPD related mortality). Current smokers had a higher risk of total mortality compared to lifetime nonsmokers: the relative risks (RR) ranged between 1.2 for male pipe smokers and 2.4 for female plain cigarette smokers. With regard to lung cancer mortality, the RR ranged between 4.1 for male pipe smokers and 7.9 for female plain cigarette smokers. Even higher RR values were estimated for COPD related mortality. In both sexes, the RR for the investigated end-points were lower in cheroot/cigar smokers and in pipe smokers than in cigarette smokers, but these differences were markedly diminished after an adjustment for the inhalation habit. The present study substantiates the view that tobacco smoking increases pulmonary and total mortality. The small differences between the various types of tobacco are probably caused by different inhalation patterns.
Frequency response of variable orifice type peak flow meters: requirements and testing
Authors: OF Pedersen, TR Rasmussen, SK Kjaergaard, MR Miller, PH Quanjer
Journal: European Respiratory Journal (1995)

Little is known about the response of variable orifice peak flow meters to high frequency flow input. The purpose of this study was to define and test dynamic requirements for such peak flow meters. In a population sample we measured peak expiratory flow (PEF), rise time (tr), from 10-90% PEF and the duration of the flow in excess of 97.5, 95 and 90% of PEF, by use of a carefully calibrated Fleisch pneumotachograph with known and adequate frequency response. Three peak flow meters (Mini Wright, Vitalograph and Ferraris) were tested with an explosive decompression calibrator adjusted to values for PEF and tr as close as possible to the 95th and 5th percentile values, respectively, both for males and females, and with peak durations between 5 and more than 100 ms. The 95th percentile values of PEF were 597 L.min-1 for females and 894 L.min-1 for males. The 5th percentile values of tr were, respectively 55 and 45 ms. The duration of flow in excess of 95% PEF was longer than 10 ms in 99% of the subjects. For all meters, the deviation of PEF corrected for alinearity were less than 5% at a peak duration of 10 ms. We conclude that PEF, rise time, and peak duration can be used for description of dynamic properties of variable orifice meters, and that the tested meters had a satisfactory frequency response for recording PEF in mostly normal subjects.
Abstract P1128: Myocardial Delivery Of Modified Mrna For Exosomal Protein Induces Cardiac Regeneration
Authors: Ajit Magadum, Vandana Mallaredy, Rajika Roy, Chunlin Wang, Darukeshwara Joladarashi, Charan Thej Gurrala, Zhongjian Cheng, May Truongcao, Anna Maria Lucchese, Cindy Benedict, Vagner O Rigaud, Mohsin Khan, Raj Kishore
Journal: Circulation Research (2022)

Permanent loss of cardiomyocytes (CM) after myocardial infarction (MI) and limited cardiac regenerative capacity leads to heart failure. Recent studies from zebrafish, newt, and even 1-day old neonatal mice showed that they could regenerate their heart through inducing existing CM proliferation. Attempts have been made to transiently reconstitute embryonic signaling in adult hearts, including overexpression of cell cycle activating genes with limited success. iPSC-derived extracellular vesicles (EV)/exosomes have been shown to improve cardiac function and some degree of CM renewal. However, the iPSC-EVs-mediated cardiac regeneration mechanism remains unclear and largely pertains to microRNAs and other RNAs, but not the proteins. Our hypothesis is the myocardial delivery of iPSC-EV-specific protein improves cardiac function and remodeling post-MI by activating pro-proliferative and anti-oxidative stress molecular pathways. Our preliminary studies showed that hiPSC-EVs induced the CM cell cycle in mice post-MI, and by employing a proteomic approach, we found a novel protein exclusively expressed in iPSC-EVs. The overexpression of hiPSC-EV enriched protein in the form of modRNA (modified mRNA) induces a robust CM cell cycle in rat neonatal CMs and in heart post-MI. By employing cardiomyocyte specific MADM (Mosaic Analysis of Double Markers) mice we showed that EV-protein induced robust cardiomyocyte division post-MI. This increase in the CMs proliferation by the modRNA was associated with reduced scar size, improved cardiac function, and mice survival 28 days post-MI. Moreover, we show that the YAP, a master regulator of CM proliferation and cardiac regeneration, binds to the promoter of the protein and induces its expression. Furthermore, using the siRNA and modRNA (inhibition and over-expression respectively) approach, we found that the protein-induced Yap1-β-catenin molecular pathway stimulates CM proliferation. Furthermore, the overexpression protein inhibited the oxidative stress or ROS analyzed by HPLC and DNA damage response post-MI. As a result of it, we have seen a significant reduction in CM apoptosis post-MI. Taken together we see the myocardial injection of iPSC-EV specific protein through a highly therapeutic modRNA tool improve cardiac function by inducing CMs proliferation, inhibiting oxidative stress, and reactivating cardiac regeneration post-injury.
Abstract P2072: Complex Remodeling Of Transcriptomes And Chromatin Accessibility Epigenomes In Acute Post-infarct Myocardium Revealed By Massive Parallel Single-nucleus Sequencing Analyses
Authors: Ba Thong Nguyen, Lovina Abdi, Robb MacLellan, Zhang Zhenhe, Yiqiang Zhang
Journal: Circulation Research (2022)

Background: Adverse remodeling in post-infarct myocardium includes weakened contractility due to substantial cardiomyocyte (CM) loss, augmented inflammatory and fibrotic responses, and re-organization of vasculatures. Current mechanistic understanding of cellular interaction within and between cardiac cell populations in post-injured myocardium remained limited. Aims: To identify molecular regulations converged in post-infarct heart cells. Methods and Results: We simultaneously analyzed total heart cells in post-infarct myocardium by using the latest single-nucleus (sn) dual transcriptomics-epigenomics approaches (snRNA-seq and snATAC-seq) in our new triple-transgenic multi-reporter mouse model featuring CM lineage tracking and maturity visualization. The compositions of cell types clustered based on transcriptomic profiles are highly comparable to those identified by open chromatin accessibility. There were significant reductions of CMs and endothelial cells, along with remarkable increases of immuno/inflammatory cells and cardiac fibroblasts in post-infarct hearts compared to controls, as revealed by comparable cell populations clustered based on transcriptomic profiles versus epigenomics chromatin accessibility profiles. We characterized the dual-omic molecular signatures of all heart cell populations from acute post-infarct murine hearts in contrast to controls. We identified the features as various molecular states in pseudotime trajectory, distinguishing each cell population and sub-cluster presented in diseased and normal hearts. Heart cells in post-infarct myocardium were clustered along the newer pseudotime series while those in control hearts were mostly located in earlier phases of the pseudotime trajectory. Lastly, we identified the signaling pathways and TFs enriched by differentially-expressed genes (DEGs) and the differentially active regions (DARs) of the chromatin in dedifferentiated CMs as well as other heart cell types and their relationships in post-MI and normal hearts. Conclusions: The results demonstrated the complex cellular and molecular remodeling at single-cell (nucleus) level in acute post-infarct hearts in which diverse and converging signaling networks may be targeted for heart failure therapeutics.
Abstract P2032: Cardiac Nuclear Receptor Subfamily 4 Group A Member 2 Activates Cell Cycle Progression And Induces Heart Failure
Authors: Sadia Ashraf, Heinrich Taegtmeyer, Romain Harmancey
Journal: Circulation Research (2022)

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiological implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to left ventricular hypertrophy and dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting polyploidization and multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.